NM_014444.5(TUBGCP4):c.1746G>T (p.Leu582=) AND Microcephaly and chorioretinopathy 3

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Jul 17, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000170357.16

Allele description [Variation Report for NM_014444.5(TUBGCP4):c.1746G>T (p.Leu582=)]

NM_014444.5(TUBGCP4):c.1746G>T (p.Leu582=)

Genes:

TUBGCP4:tubulin gamma complex component 4 [Gene - OMIM - HGNC]
TP53BP1:tumor protein p53 binding protein 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q15.3

Genomic location:

Preferred name:

NM_014444.5(TUBGCP4):c.1746G>T (p.Leu582=)

Other names:

p.Leu582Leu

HGVS:

NC_000015.10:g.43403697G>T
NG_042168.1:g.37639G>T
NG_042168.2:g.37598G>T
NM_001141979.3:c.*3686C>A
NM_001141980.3:c.*3686C>AMANE SELECT
NM_001286414.3:c.1749G>T
NM_001355001.2:c.*3686C>A
NM_001411050.1:c.*3686C>A
NM_005657.4:c.*3686C>A
NM_014444.5:c.1746G>TMANE SELECT
NP_001273343.1:p.Leu583=
NP_055259.2:p.Leu582=
NC_000015.9:g.43695895G>T
NM_001286414.2:c.1749G>T
NM_014444.2:c.1746G>T
NM_014444.3:c.1746G>T
NM_014444.4:c.1746G>T

Nucleotide change:

1746G-T

Links:

OMIM: 609610.0001; dbSNP: rs200092283

NCBI 1000 Genomes Browser:

rs200092283

Molecular consequence:

NM_001141979.3:c.*3686C>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001141980.3:c.*3686C>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001355001.2:c.*3686C>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001411050.1:c.*3686C>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_005657.4:c.*3686C>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001286414.3:c.1749G>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_014444.5:c.1746G>T - synonymous variant - [Sequence Ontology: SO:0001819]

Condition(s)

Name:: Microcephaly and chorioretinopathy 3
Synonyms:: Microcephaly and chorioretinopathy, autosomal recessive, 3
Identifiers:: MONDO: MONDO:0014592; MedGen: C4225362; OMIM: 616335

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000222766	OMIM	no assertion criteria provided	Pathogenic (Apr 2, 2015)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001139564	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001522223	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 4, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002070491	Genetic Services Laboratory, University of Chicago	no assertion criteria provided	Pathogenic (Jul 26, 2018)	germline	clinical testing
SCV002538640	Laboratory of Human Genetics, Universidade de São Paulo	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 27, 2022)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV005086148	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 17, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25817018, 35418825, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in TUBGCP4 alter microtubule organization via the γ-tubulin ring complex in autosomal-recessive microcephaly with chorioretinopathy.

Scheidecker S, Etard C, Haren L, Stoetzel C, Hull S, Arno G, Plagnol V, Drunat S, Passemard S, Toutain A, Obringer C, Koob M, Geoffroy V, Marion V, Strähle U, Ostergaard P, Verloes A, Merdes A, Moore AT, Dollfus H.

Am J Hum Genet. 2015 Apr 2;96(4):666-74. doi: 10.1016/j.ajhg.2015.02.011. Epub 2015 Mar 26.

PubMed [citation]

PMID:: 25817018
PMCID:: PMC4385181

Bi-Allelic c.1746G>T; p.Leu582= Variants in TUBGCP4 in a Boy with Autism: Clinical Data and Literature Review.

Martín Fernández-Mayoralas D, Albert J, López-Martín S, de la Peña MJ, Fernández-Perrone AL, Jiménez de Domingo A, Calleja-Pérez B, Martínez-García M, Álvarez S, Fernández-Jaén A.

Mol Syndromol. 2022 Feb;13(2):165-170. doi: 10.1159/000519365. Epub 2021 Dec 2.

PubMed [citation]

PMID:: 35418825
PMCID:: PMC8928183

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000222766.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 4 French children from 3 unrelated families with autosomal recessive microcephaly and chorioretinopathy-3 (MCCRP3; 616335), Scheidecker et al. (2015) identified a synonymous c.1746G-T transversion (c.1746G-T, NM_014444.2) in exon 16 of the TUBGCP4 gene in compound heterozygosity. The other TUBGCP4 allele carried a c.579dupT (609610.0002), deletion of exons 16-18 (609610.0003), or c.298delT (609610.0004). The c.1746G-T transversion was predicted to act as a strongly activated cryptic acceptor splice site, resulting in the skipping of exon 16 and generation of an unstable mRNA, as demonstrated in patient cells. Mutations in the first 2 families were found by exome sequencing; mutations in the third family were found by Sanger sequencing of 12 additional French patients with a similar disorder. The c.1746G-T mutation was found at a frequency of 0.00036 in the Exome Variant Server and Exome Aggregation Consortium databases. Skin fibroblasts from 1 patient showed a reduction of TUBGCP4 protein to about 40% of control values; the protein was decreased in the centrosomes, both in interphase and during mitosis. Levels of all other components of the gamma-tubulin complex were also decreased.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV001139564.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001522223.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV002070491.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

DNA sequence analysis of the TUBGCP4 gene demonstrated a synonymous pathogenic sequence change, c.1746G>T p. Leu582Leu, in exon 16, that does not result in an amino acid substitution. This silent sequence change was previously reported in in the compound heterozygous state in a patient with TUBGCP4-related microcephaly and chorioretinopathy (PMID: 25817018). Functional analysis of individual fibroblasts demonstrated that the c.1746G>T variant resulted in skipping of exon 16, which led to a reduction of the protein product (PMID: 25817018).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Human Genetics, Universidade de São Paulo, SCV002538640.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		not provided	not provided	not provided	research	PubMed (1)

Description

This variant meets our criteria to be classified as pathogenic based upon segregation studies, low frequency in control samples, and in-silico evaluation of pathogenicity.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086148.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with microcephaly and chorioretinopathy, 3, (MIM#616335). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. RT-PCR of cDNA derived from an affected individual's fibroblasts has demonstrated this variant causes inframe exon 16 skipping, but also the retention of wildtype protein. The proportion of wildtype and mutant protein is unclear (PMID: 25817018). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (86 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located in the annotated Gamma tubulin complex component C-terminal domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as likely pathogenic or pathogenic, and is a recurring variant observed in compound heterozygous individuals with microcephaly, chorioretinopathy and intellectual disability (ClinVar, PMID: 25817018), and a homozygous individual with autism and ectasia of the optic nerve sheaths with no microcephaly or chorioretinopathy (PMID: 35418825). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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